Formation of (cis) heptachlor epoxide



United States Patent 3,155,689 FORMATIQN 6F (CIS) HEPTACHLUR EPGXIDE William B. Burton, Modesto, Calif assignor to Sheli Oil Company, New York, N.Y., a corporation of Delaware N0 Drawing. Filed Nov. 7, 1960, Ser. No. 67,501 6 Claims. (Cl. 269-3485) This invention pertains to a synthetic method for the preparation of the stereoisomeric form of heptachlor epoxide which in biological systems is formed from heptachlor.

It has been found that in biological systems, heptachlor (that is, l,4,5,6,7,8,8-heptachloro-3a,4,7,7a-tetrahydro-4, 7-methanoindene) is converted to an epoxide (that is, 2, 3 epoxy 1,4,5,6,7,8,8 heptachloro 2,3,3a,4,7,7ahexahydro-4,7-methanoindene) (M.P. 157-159.5 C.) Davidow et al., 106 Journal of Pharmacology and Experimental Therapeutics 259 et seq. (1952). That epoxide, commonly known as metabolite heptachlor epoxide, has been found to be a potent insecticide, and to be about ten times as toxic with respect to the housefly as a heptachlor epoxide prepared synthetically. (US. Dept. Health, Education, and Welfare, Public Health Service, Communicable Disease Center, Technology Branch, Summary of Investigations No. 7, July-December 1954, p 90.) The synthetic heptachlor epoxide is prepared by the method set out in British Patent No. 714,869, Complete Specification published September 1, 1954. The method involves addition of the elements of hypochlorous or hypobromous acid to heptachlor, and then dehydrochlorinating or dehydrobrominating the product to give an epoxide (MP. 83-85 (3.).

Although complete studies have not been made, on available evidence it is believed that the metabolite and synthetic epoxides are spatial isomers, and that the diiference in spatial configuration causes the difference in biological activity of the two compounds. It is believed that the metabolite epoxide is the cis isomer that is, it is the isomer in which spatially the epoxide ring lies on the same side of the five-membered ring as do the hydrogen atoms at the 3a and 7a positionsand it is believed that the synthetic epoxide is the trans isomer. In terms of spatial configuration, it is therefore believed that the metabolite epoxide has the structure set out schematically in Formula I, While the synthetic epoxide has the structure set out schematically in Formula II.

In the interest of clarity, heptachlor epoxide has the planar formula 3,155,689 Patented Nov. 3., 1964 ice In these isomers, it will be noted that the chlorine atom in the 1-position is cis with respect to the angular hydrogen atoms-that is, the hydrogen atoms in the 3aand 7a-positions-and that both isomers have the endo configuration of the methano-bridged ring with respect to the fixe-membered ring. In the metabolite epoxide the epoxy bridge is cis with respect to the angular hydrogen atoms, while in the synthetic isomer the epoxy bridge is trans with respect to the angular hydrogen atoms.

I now have discovered a process for synthesizing the metabolite epoxide isomer. In brief, I have found that the metabolite isomer is formed by the chromic acid oxidation of heptachlor at a temperature not exceeding about 100 C.

The oxidation is carried out by any of the usual techniques for employing chromic acid (chromium trioxide) as a mild oxidizing agent. Thus, in general, the chromic acid is slowly added to, or is gradually formed in the presence of, the heptachlor dissolved in a suitable liquid reaction medium to moderate the strength of the chromic acid as an oxidizing agent. That is to say, the preformed chromic acid can be used, or the acid can be formed in situ in the reaction mixture, as will be described in greater detail hereinafter.

It is generally desirable to include in the reaction mixture a lower carboxylic acid, such as acetic acid, or the anhydride of such an acid, such as acetic anhydride, since these materials desirably affect the oxidizing properties of the chromic acid. In some cases, it will be found most convenient to employ such an acid or anhydride to provide the necessary fluid reaction medium; in other cases, it may be found most desirable to include another, inert liquid, as solvent. For this purpose, such materials as carbon tetrachloride or other halogenated lower alkane, carbon disulfide, or other solvents of like properties, are suitable. In general, it will be found desirable to exclude substantial amounts of water from the reaction zone; small amounts of water can be tolerated.

The amount of carboxylic acid or anhydride used should be at least sufiicient to dissolve the heptachlor and the heptachlor epoxide that is formed, thus maintaining a homogeneous organic liquid reaction phase, and it will usually be found desirable to employ a substantial excess of the acid or anhydride. Where acetic acid or acetic anhydride is employed, at least about seven parts by volume of the acid or anhydride should be used per part by weight (parts by volume bearing the same relation to parts by weight as does the liter to the kilogram) of hept-achlor used, and preferably somewhat moreeight to ten parts by volume, or even moreof the acid or anhydride is used. Where another solvent is employed, it preferably is substituted only in part for the acid or anhydride, the primary criterion being the maintenance of a homogeneous organic liquid reaction phase. Where such another solvent is employed, it still will be generally desirable to include at least three and preferably five or more parts by volume of carboxylic acid or anhydride per part by weight of heptachlor used.

Since chromic acid can be a powerful oxidizing agent and can oxidize the heptachlor epoxide to the corresponding di-acid, the epoxidation reaction is conducted at a temperature not exceeding about 100 C., and preferably temperatures not exceeding about C. are used, to minimize the possibility of such further oxidation. Any lower temperature which is suitable from the physical character of the reaction medium-it should remain homogeneous and liquid, of course-can be used. Ordinarily, temperatures below 10 C. will not be found of advantage. If desired, the addition of the chromic acid to the heptachlor solution can be conducted at a temperature within the upper end of the desirable range, and the further reaction also conducted at that temperature. However, it usually will be found more desirable, since control of the reaction temperature is more easily accomplished, to mix the chromic acid with the heptachlor solution at a low temperature, say from 10 C. to 25 C., allowing the heat evolved in the exothermic oxidation to heat the reaction mixture, then heat the reaction mixture, with stirring, at a higher temperature within the desirable range to insure completion of the oxidation. The reaction mixture should be maintained for the minimum time required to effect the oxidation.

At least the stoichiometric amount of chromic acid is employed, but it will be desirable in many if not most cases to avoid use of more than a small-for example, a 5-10 percent-excess, to reduce the possibility of oxidation of the heptachlor epoxide.

Where the chromic acid is formed in situ in the reaction mixture, this is most conveniently done by reacting an alkali metal chromate or dichromatefor example, sodium or potassium chromate or dichromate-with strong sulfuric acid. The reaction is essentially quantitative. While the chromic acid can be formed by adding the sulfuric acid to the heptachlor solution and then adding the alkali metal chromate or dichromate, preferably, the reverse order of addition is employed. Still more preferably, to moderate the action of the chromic acid, the acid is formed gradually, by slow addition of one reactant to the other.

Because of the smoothness with which the oxidation of heptachlor can be carried out to give high yields of the epoxide, it is preferred to conduct the oxidation by the so-called chromic acid-sulfuric acid technique, wherein at least the latter stages of the oxidation are conducted in the presence of strong sulfuric acid. For this purpose, as well as to minimize the amount of water in the reaction mixture, it is desirable that the concentration of the sulfuric acid used be at least 50 percent by weight. Commercial concentrated sulfuric acid-93-98 percent by weight H S is suitable and often most convenient. At least about 2 moles of such sulfuric acid (as H 50 should be provided per mole of chromic acid, and preferably there are used 'from about 5 to about or even more moles of sulfuric acid per mole of chromic acid used. Since the sulfuric acid need not be entirely present except in the latter stages of the oxidation, the oxidation can be conducted by mixing the heptachlor, liquid reaction medium and alkali metal chromate or dichromate, then adding strong sulfuric acid slowly to form the chromic acid and then also to provide the necessary sulfuric acid.

The oxidation ordinarily is completed in a short timeof the order of minutes or lessafter all of the reactants have been mixed, which mixing ordinarily will require from about 15 minutes to about one hour. The reaction mixture then is quenched with water, preferably chilled water, such as ice water. A volume of water equal to that of the final reaction mixture ordinarily is sufficient, but more orless than this volume may be used in some cases. The epoxide then is recovered by the usual means, extraction of the mixture with ether being one satisfactory method. The epoxide then is purified by crystallization or other orthodox techniques.

The process of the invention is illustrated by the following example, which shows one typical application of the process. In the example, p.b.w. means parts by weight, p.b.v. means parts by volume, and parts by weight bear the same relationship to parts by volume as does the kilogram to the liter.

To a solution of 6.54 p.b.w. of heptachlor in 56 p.b.v. of glacial acetic acid there was added 7.78 p.b.w. of potassium dichromate. The mixture was stirred and 14 p.b.v. of concentrated sulfuric acid was added dropwise over a period of 30 minutes. The temperature of the mixture rose to 55 C. After the addition was complete, the reaction mixture was heated at C. for 5 minutes with stirring. The reaction mixture then was cooled and poured into an equal volume of ice water, and the resulting mixture was extracted with several portions of ether. The combined ether extracts were washed with water, 10% w. sodium hydroxide solution, and again with water. After drying with anhydrous sodium sulfate and charcoaling, the ether solution was evaporated to give 5.5 p.b.w. of crude product. Two successive recrystallizations from ethyl alcohol gave 4.3 p.b.w. of analytically pure material melting at 164.5 C.

Analysis:

Percent Percent Percent w. C W. If \v. 01

Calculated 30. 8 1.3 03. 9 Found 31. 2 1.6 03. 7

Analysis:

Percent Percent \v. Br \v Cl Calculated 17.0 52. 8 Found l7. 5 53. 2

The bromohydrin then was converted back to the heptachlor epoxide: 84 milligrams of the heptachlor brornohydrin, 21 milligrams of potassium hydroxide, and 2 milliliters of ethanol were heated at reflux for 6 hours. Recrystallization from ethyl alcohol gave 75 milligrams of product, melting at 163 C., undepressed upon admixture with heptachlor epoxide prepared as set out hereinbefore. The infrared spectrum showed a peak at 11.68 microns.

The product of the foregoing process was identified as the metabolite isomer by entomological evaluation, wherein it was found to possess the very high insecticidal activity which the art has shown that the metabolite isomer possesses.

I claim as my invention:

1. The liquid phase process for preparing the metabolite isomer 2,3-epoxy-l,4,5,6,7,8,8-heptachloro-321,4,7, 7a-tetrahydro-4,7-methanoindene by subjecting 1,4,5,6,7,8, 8-heptachloro-3a,4,7,7aatetrahydro-4,7-methanoindene to the oxidizing action of chromic acid at a temperature of from about 10 C. to about C.

2. The liquid phase process for preparing the metabolite isomer 2,3-epoxy-l,4,5,6,7,8,8-heptachloro-3a,4,7, 7a-tetrahydro-4,7-methanoindene by subjecting 1,4,5,6,7,8, 8-heptachloro-3a,4,7,7a-tetrahydro-4,7-methanoindene to the oxidizing action of chromic acid in the presence of a member of the group consisting of lower alkane monocarboxylic acids and anhydrides thereof at a temperature of from about 10 C. to about 100 C. in the presence of strong sulfuric acid.

3. The liquid phase process for preparing the metabolite isomer 2,3-epoxy-1,4,5,6,7,8,8-heptachloro-3a,4,7, 7a-tetrahydro-4,7-methanoindene by subjecting l,4,5,6,7,8, 8-heptachloro-3a,4,7,7a-tetrahydro-4,7-methanoindene to the oxidizing action of at least a stoichiometric amount of chromic acid in the presence of a substantial excess of SE a member selected from the group consisting of lower alkane monocarboxylic acids and anhydrides thereof at a temperature of from about 10 C. to about 100 C. in the presence of at least 50 percent by weight of strong sulfuric acid.

4. The liquid phase process for preparing the metabolite isomer 2,3-epoxy-1,4,5,6,7,8,8-heptachloro-3a,4,7, 7a-tetrahydro-4,7-methanoindene by subjecting 1,4,5,6,7,8, 8-heptachloro-3a,4,7,7a-tetrahydro-4,7-rnethanoindene to the oxidizing action of from about to about 10 percent excess of chromic acid in the presence of a member selected from the group consisting of lower alkane monocarboxylic acids and anhydrides thereof with at least about seven parts by volume of the acid and anhydride per part by weight of 1,4,5,6,7,8,8-heptachloro-3a,4,7,7a-tetrahydro-4,7-methanoindene, at a temperature of from about 10 C. to about 85 C., in the presence of from about 5 to about moles of strong sulfuric acid per mole of chromic acid.

5. The liquid phase process for preparing the meta bol'ite isomer 2,3-epoxy-1,4,5,6,7,8,8-heptachloro-3a,4,7, 7a-tetrahydro-4,7-methanoindene by subjecting 1,4,5,6,7,8, 8-heptachloro-321,4,7,7a-tetrahydro-4,7-methanoindene to the oxidizing action of chromic acid in the presence of a substantial excess of a member selected from the group consisting of lower alkane monocarboxylic acids and anhydrides thereof at a temperature of from about 10 to about 100 C. and in the presence of at least percent by Weight of strong sulfuric acid, the chromic acid being formed in situ in the reaction mixture containing a member of the group consisting of alkali metal chromates and dichrom-ates by the gradual addition thereto of strong sulfuric acid.

6. The liquid phase process for preparing the metabolite isomer 2,3-epoxy-1,4,5,6,7,8,8-heptachloro-3a,4,7, 7a-tetrahydro-4,7-methanoindene by subjecting 1,4,5,6,7,8, 8-heptachloro-3a,4,7,7a-tetrahydro-4,7-methanoindene to the oxidizing action of from about 5 to about 10 percent excess of chromic acid in the presence of a member selected from the group consisting of acetic acid and acetic anhydride thereof in at least about seven parts by volume of the acid and anhydride per part by Weight of 1,4,5,6,7,8,8-heptachloro-3a,4,7,7a-tetrahydro 4,7 meth- -anoindene,at a temperature of from about 10 to about C., in the presence of from about 5 to about 20 moles of strong sulfuric acid per mole of chromic acid.

References Cited in the file of this patent UNITED STATES PATENTS 2,583,569 Herzfeld et a1. Jan. 29, 1952 2,623,888 Nichols Dec. 30, 1952 2,676,131 Soloway Apr. 20, 1954 2,793,975 Mark May 28, 1957 2,873,283 Yang Feb. 10, 1959 OTHER REFERENCES Hickinbottom et al.: J. Chem. Soc., London (1957), pages 4195-8.

Lowry: Inorganic Chemistry, Macmillan & Co., Ltd., London (1931), pp. 1012-1014. 

1. THE LIQUID PHASE PROCESS FOR PREPARING THE METABOLITE ISOMER 2,3-EPOXY-1,4,5,6,7,8,8-HEPTACHLORO-3A,4,7, 7A-TETRAHYDRO-4,7-METHANOINDENE BY SUBJECTING 1,4,5,6,7,8, 8-HEPTACHLORO-3A,4,7,7A-TETRAHYDRO-4,7-METHANOINDENE TO THE OXIDIZING ACTION OF CHROMIC ACID AT A TEMPERATURE OF FROM ABOUT 10*C. TO ABOUT 100*C. 